DESCRIPTION (applicant's abstract): Destruction of articular cartilage through disease processes such as inflammatory arthritis and osteoarthritis causes significant pain and disability. The normal balance between anabolic and catabolic processes is altered so that chondrocyte synthesis of matrix components cannot compensate for the increased rates of degradation found in these conditions. The effects of superoxide dismutase on articular cartilage homeostasis has not been systematically studied. Exploratory studies using extracelluar superoxide dismutase (EC-SOD) knock-out and transgenic mice originally developed for evaluating the pathogenesis of pulmonary fibrosis to examine these relationships are proposed. The long term goal is to explore the potential chondroprotective effects of EC-SOD. The working hypothesis is that EC-SOD plays a central role in protecting against cartilage degradation in the arthritic joint. To test the hypothesis that EC-SOD plays a central role in protecting against articular cartilage loss in the arthritic joint by comparing the structural and metabolic responses of articular cartilage following zymosan induced gonarthritis between wild-type, EC-SOD knockout mice which cannot produce EC-SOD, and EC-SOD transgenic mice which produce excess EC-SOD. Studies in experimental models of arthritis have implicated nitric oxide (NO) as an important pathogenic factor. EC-SOD may prevent the reaction of NO with superoxide to form peroxynitrite, a potent oxidant which may account for some of the damaging effects of NO. Interleukin-l (IL-l) inhibition of proteoglycan synthesis has been linked to the presence of NO. To test the hypothesis that prevention of peroxynitrite formation is one mechanism by which EC-SOD protects against IL-1 inhibition of carnage repair, we plan to compare NO production, nitrotyrosine immunoreactivity, matrix metalloproteinases, and proteoglycan synthesis between wild-type, EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. IL-l has been associated with development of chondrocyte insensitivity to the anabolic actions of Insulin-like Growth Factor-I (IGF) in both in vitro and in vivo models of arthritis. In contrast to wild-type mice, iNOS knockout mice maintain their anabolic response to IGF-1 following intra articular injection of IL-1. This implicates NO and NO derivatives such as peroxynitrite as critical, factors in the development of chondrocyte insensitivity to IGF-1 in the arthritic joint. To test the hypothesis that peroxynitrite is the reactive species involved in IL-1 induced chondrocyte unresponsiveness to the anabolic effects of IGF-1, we plan to compare NO production, nitrotyrosine immunoreactivity, and proteoglycan synthesis in the presence of IGF-1 between wild-type EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. The proposed studies will advance the current knowledge base on the effects of EC-SOD in modulating cartilage degradation in the arthritic joint. These studies will also serve to improve understanding of the relative roles of NO and peroxynitrite on the pathophysiology of arthritis.